Field of the Invention
The present invention relates to a method for inducing hematopoietic cell differentiation and maturation and, more particularly, to an in vitro production of erythrocytes and a treatment of myelodysplastic syndromes using a method for inducing erythrocyte differentiation and maturation.
Background of Technique
The increased demands on medical care from the rapid aging of the population and the development of scientific technology cause an increased use of erythrocytes for transfusion, resulting in a great shortage of erythrocytes. In addition, outbreaks of diseases, such as mad cow disease, swine flu, and malaria significantly reduced people allowing blood donation. Hence, the lack of blood required for transfusions domestically and world widely is causing a setback for patient surgery and treatment. However, this lack of blood will get more serious in the future, and thus it is expected that 55.5% of the domestic blood required will be insufficient (Korea Institute for Health and Social Affairs, 2005). Moreover, transfusion-transmitted infection that may occur due to transfusion causes serious problems in donors, and although founding the problems in advance is hugely expensive, the infection cannot be completely detected (Timmins, N. E.; Nielsen, N. K. Manufactured RBC—Rivers of blood, or an oasis in the desert? Biotechnology Advances 29(6):661-6(2011)). These factors have increased the need for the development of stable erythrocytes that are artificially produced (Olsson, M. L.; Clausen, H. Modifying the red cell surface: towards an ABO-universal blood supply. Br. J. Haematol. 140:3-12; 2008).
FIG. 1 is a diagram illustrating the erythrogenic process. Referring to FIG. 1, the erythroblast matures into a basophilic erythroblast, a polychromatic erythroblast, an orthochromatic erythroblast, and then a reticulocyte. For forming the reticulocyte lastly, an enucleation procedure for efflux of the cell nucleus is needed, and involves the remodeling of the plasma membrane and cytoskeleton. Cytoskeletal proteins, such as spectrin, microtubules, vimentin, and actin filament (F-actin), are involved in this procedure. In addition, the actin filament binds with various proteins (protein 4.1, protein 4.9, spectrin, adducing, tropomysin, tropomodulin, etc.) to make membrane skeleton junctions, thereby forming a surface of the mature erythrocyte. However, most researches relating to the production of artificial blood derived stem cells have merely focused on the amplification of stem cells and progenitor cells until now, and causes and alternatives for the slow maturation of mature cells, a low enucleation rate, low cell viability, and myelodysplasia as one of the factors that induce the low enucleation rate and low cell viability, at the latter half which is the most important and hard stage, have not been known, and researches thereof are insufficient. The cell dysplasia is a very important research subject in order to understand diseases that originate in erythropoiesis and hematopoiesis. The cell maturation, enucleation, and the like at the latter half normally occur in in vivo erythropoiesis, and are necessary for being completed into erythrocytes. For the in vitro production of transfusable artificial erythrocytes, it is necessary to reproduce an in vivo mimiced environment in which the above problems are efficiently controlled in normal situations.
Meanwhile, myelodysplastic syndromes are a group of clonal malignant blood diseases characterized by inefficient hematopoiesis due to progressive pancytopenia and abnormal cell differentiation/maturation. This disease often shows the chronic progress over several years and leads to acute leukemia. The myelodysplastic syndrome involves various molecule abnormalities, which appear in various forms, such as changes in cell cycle and apoptosis, DNA methylation, changes in cancer genes, and changes in bone marrow microenvironments. The incidence of myelodysplastic syndrome is higher than that of normal leukemia, but currently has been underestimated. The median age of onset of this disease has been reported to be the age of 70 in western countries, and as the age increases, the frequency of the disease also increases. One of the 2006 researches reported approximately 12,000 new patients each year in the United States. According to the National Health Insurance Corporation statistics, there were 1845 domestic patients, and approximately 600 new patients are found each year.
The best supportive care has been traditionally employed for the treatment of the myelodysplastic syndrome, and chemotherapy and allogeneic hematopoietic stem cell transplantation have been implemented in the high-risk group patients. However, the average time of survival is only 22 months, and when compared with the survival times by risk groups of patients with lung cancer and stomach cancer, the myelodysplastic syndrome is very severe so that the mid-term survival is similar between the two diseases, and the prognosis of the myelodysplastic syndrome is only 0.4 to 5.7 years. Over the past five years, new concepts of targeted therapeutic agents has changed conditions of the disease and improved the viability, and thus are emerging as new therapies substituting for the best supportive care which has been a therapeutic principle until now, and the efforts for combination therapy with various drugs are being continuously made. These efforts lead to the continuous development of therapeutic agents that are effective in the treatment of the myelodysplastic syndrome, but the percent of patients responding to the therapeutic agents does not exceed 40% for even the best therapeutic agent. Therefore, in the future, fundamentally, the therapeutic agents responding to causes of the myelodysplastic syndrome need to be developed in the future and the therapeutic agents through protein stimulation needs to be developed instead of hematopoietic stem cell transplantation that cannot be implemented on most old age patients.